Dissertations / Theses on the topic 'Lymphome diffus à grandes cellules B (DLBCL)'
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Boudesco, Christophe. "Expression et rôle d’HSP110 dans le lymphome B diffus à grandes cellules de type activé ou ABC-DLBCL." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI014.
Full textHeat shock proteins (HSPs) are highly conserved protein across species, and are expressed in all cell type. HSPs are molecular chaperones involved in the folding of newly synthesized or denaturated proteins. HSPs are overexpressed in cancer cells, where they contribute to cancer resistance to chemotherapies. Among HSPs, roles and functions of HSP110 are less described. Interestingly, HSP110 was recently associated with lymphoma aggressiveness in Diffuse Large B Cell Lymphoma (DLBCL). DLBCL is the most lymphoproliferative disease diagnosed in adult (30% of Non-Hodgkin Lymphoma). Three main subtypes of DLBCL are described: Activated-B-Cell lymphoma (ABC-DLBCL), Germinal Center lymphoma (GC-DLBCL), and Primary Mediastinal B Lymphoma (PMBL). ABC-DLBCL is the most aggressive form associated with a poor prognosis. Even if R-CHOP therapies had improve patient’s survival over the last decades, most of patients experiences relapses or treatment resistances. New molecular target are now necessary to treat efficiently these subtypes.My PhD work has highlighted the role of HSP110 in the NFkB signaling pathway, which is an oncogenic pathway in ABC-DLBCL. First, we show that HSP110 is overexpressed in ABC-DLBCL patient sample. We also show an interaction between HSP110 and Myd88 L265P, that is an oncogenic protein responsible for NFkB pathway activation. Consequently, HSP110 stabilizes Myd88 L265P, leading to a sustain NFkB pathway activation in lymphoma cells, and promoting ABC-DLBCL cell survival and proliferation.Finally, our team recently characterized the first known HSP110 inhibitors. I took the opportunity to test these putative inhibitors in my study. My results suggest that these compounds have similar effects than siRNA or shRNA inhibition of HSP110 on ABC-DLBCL survival. This result provide a ground for future in vivo testing of chemical inhibitors of HSP110.In conclusion, my work highlight HSP110 as a potential therapeutic target in ABC-DLBCL
Bentayeb, Hafidha. "Résistances/sensibilisations aux anti-CD20 (rituximab) dans les lymphomes diffus à grandes cellules B (DLBCL)." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0072/document.
Full textDiffuse large B cell Lymphomas (DLBCL) are the most aggressive and heterogeneous biological and clinical form of non-Hodgkin lymphomas in adults. Although more than 50% of patients can be cured with standard therapy R-CHOP (combining the CHOP chemotherapy to the anti-CD20 as rituximab) 30 to 40% of patients exhibit primary refractory disease or relapse after initial response to therapy, determining morbidities and significant mortality related to the limited number of treatment options. The aim of this thesis was focussed on therapeutic resistances of these lymphomas, notably those of rituximab. In the first part of this thesis, we have evaluated the role of endogenous factor signaling, the neurotrophins (NTs), in DLBCL cell survival and sensitivity to the cytotoxicity of rituximab. We showed first that a high expression of neurotrophines (NGF, BDNF) and their high (Trk) and low (p75NTR) affinity receptors was often found in tumor B cells of DLBCL patients. Results obtained in vitro, on human cell lines of DLBCL, but also in vivo (xenografts) showed evidence of a survival BDNF/TrkB/p75NTR axis that can interfere with the efficacy of immunotherapy. This axis promotes survival of tumor cells and may also participate in rituximab resistance in regulating CD20 expression at the surface of exosomes. Indeed, these microvesicles, secreted in large amounts by the tumoral B cells, express the CD20 and would be involved in the therapeutic escape acting as decoy receptors upon rituximab exposure. In the second part of the thesis, we evaluated in DLBCL the potential role of new oncogenic targets, PHBs proteins and the initiation factor of translation eIF4A. To this end, we used one of their ligands, a synthetic flavagline named FL3. We showed that FL3 determines a strong apoptosis in vitro on DLBCL cell lines and in vivo on tumors induced in mice (xenografts). Our works have clarified the molecular mechanisms, demonstrating involvement of PHBs, in correlation with ERK1/2 activation, and eIF4F complex formation and activity. Preliminary data obtained in patient biopsies showed a high expression of PHB1 in tumor B cells that may be decisive for cell survival and patient outcome lymphomas.Overall, present results show evidence of new survival and rituximab escape mechanisms in DLBCL, that should allow to identify new diagnostic and prognostic biomarkers for alternative therapeutic options
Arnaud, Nicolas. "Les lymphomes B diffus à grandes cellules de type activé : rôle de NF-κB et c-Myc." Thesis, Limoges, 2017. http://www.theses.fr/2017LIMO0105/document.
Full textNot only Burkitt lymphoma (BL) with the translocation of MYC, but also diffuse large B-cell lymphoma (DLBCL) by other mechanisms (mutation, amplification, promoter dysregulation…) are associated with dysregulation of c-Myc, the master transcription factor for proliferation. DLBCL’s are classified in two subgroups: “Germinal center B-cell” (GCB) without and “activated B-cell” (ABC) with constitutive NF-κB activation. This constitutive activation of NF-κB can be the result of genetic alterations (MYD88, A20, TRAF2, and TRAF5) or the activation of B-cell receptor or CD40. These features raise the question of the synergy of action between NF-κB and c-Myc in ABC-DLBCL. We analyzed the effect of a continuous activation of c-Myc in a context of over-activation of NF-κB by several inductors. Our results show that overexpression of c-Myc in the context of induction of NF-κB, i) by EBV latency III program, provides a selective advantage to those cells (gene expression in favor of a high metabolism, intense proliferation and protection against apoptosis), ii) by TLR9 (in vivo and in vitro model) increases the survival and proliferation of B lymphocytes of λc-Myc mice (increase of activated B cells, splenomegaly, increased B cells proliferation, modification of tumor microenvironment), and iii) by CD40, induces a very aggressive B lymphomagenesis in CD40/Myc double transgenic mice, the tumors have a phenotype close to ABC-DLBCL. These results suggest that c-Myc is an NF-κB co-transforming event in aggressive lymphomas with an activated phenotype by NF-κB, such as ABC-DLBCL
Moreira, Collares Davi. "An alternative way to look at diffuse large B-cell lymphoma : the impact of frequent engagement of ReIB NF-κB subunit on cell survival and patient outcome." Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB019.
Full textNF-κB transcription factors play critical role in cell proliferation, cell survival and the physiopathology of numerous cancers. Deregulation of the classical NF-κB pathway is known to be involved in at least the ABC subset of diffuse large B-cell lymphoma (DLBCL). However, the activation status of RelB NF-κB alternative pathway subunit and its role remain unclear. We have demonstrated a frequent engagement of RelB in human DLBCL-derived cell lines. RelB activation protected cells from DNA damage and apoptosis induced by doxorubicin, the main drug in DLBCL treatment. RelB also controlled the expression of the anti-apoptotic protein cIAP2. In a cohort of 66 de novo DLBCL patients, we have directly assessed the DNA binding activity of all NF-κB subunits by EMSA coupled with supershift. RelB activation was present in 66.6% of cases regardless of ABC or GCB classification and was an independent predictor of worse outcome. RelB activation status by EMSA allowed the definition of a RelB gene expression signature that was able to confirm RelB’s negative impact on patient outcome when extended to a larger cohort. Altogether, our study indicates that RelB is a potential new biomarker for DLBCL and sheds light on its important role in DLBCL cell biology
Prévaud, Léa. "Rôle de la sous-unité c-Rel NFkB dans les Lymphômes B Diffus à Grandes Cellules du Centre Germinatif (GCB-DLBCLs) : établissement d'un modèle murin préclinique." Electronic Thesis or Diss., Limoges, 2023. http://www.theses.fr/2023LIMO0108.
Full textThe transcription factor Rel/NF-kB includes 5 subunits (SU), p50, p52, c-Rel, RelA and RelB which associate into dimers. NF-κB is at the heart of the ontogeny of mature B lymphocytes in the germinal centers (GC) for c-Rel and RelB and during plasma cell differentiation for RelA. Diffuse large cell lymphoma (DLBCL) represent more than 80% of aggressive B-cell lymphomas. We have published that NF-kB SUs must be taken into account differentially, such that RelB is a marker of poor prognosis, RelA is the SU of the ABC molecular subtype (activated B cell) and cRel that of GCB (germinal center B cell)-DLBCL with a novel clean transcriptomic signature. This project consists of understanding mechanistically how c-Rel induces the transformation of a GC B lymphocyte. We have established a new mouse model of c-Rel overexpression (with YFP) in some CG B lymphocytes (tdTomato-AID-Creert2) and are testing the clonal emergence of a tumor. The originality of this inducible model relies in the fact that it makes it possible to follow the competition between the B of the GCs on expressed c-Rel (tdTomato and YFP) compared to their normal counterpart (tdTomato)
Diaz, Herrero Alba. "Characterization of Tumor Immune Microenvironment in Human Diffuse Large B-cell Lymphoma." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL057.
Full textDiffuse Large B-cell Lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin's Lymphoma worldwide, characterized by an abnormal proliferation of mature B cells. It is an aggressive B-cell malignancy for which the current therapeutic strategies are still insufficient. The tumor microenvironment (TME) is the dynamic network of cells and all elements surrounding and interacting with the tumor. It plays an important role in cancer development, treatment response, and patient survival. Consequently, investigating the TME in DLBCL patients is crucial to discover the mechanisms leading to relapse and identify prognostic biomarkers. However, its diffuse tissue structure presents a challenge in elucidating the cellular organization and communication within the TME. The objective of my Ph.D. thesis is to conduct a comprehensive multimodal characterization of the immune cells within the DLBCL tumor microenvironment.To facilitate access to human samples, I developed and implemented an ethically approved clinical research protocol and a circuit of tissue and blood samples from patients with DLBCL treated at Saint Louis hospital, ensuring that the patient cohort reflects the heterogeneity of the disease.First, I performed a deep characterization of T lymphocytes, with special focus on describing their role within the DLBCL tissue. Indeed, Tumor-infiltrating T-cells (TILS) are key players in the NHL TME, presenting different subtypes and cell states. I apply multiparametric flow cytometry and high-dimensional spectral cytometry to investigate the complex landscape of T diversity in DLBCL biopsies, as well as their communication patterns with other immune cells in the tissue. The unsupervised analysis approach identified unexpected T-cell subtypes at a protein level, compared to tissue control and other lymphoproliferative disorders. Furthermore, the ligand-receptor expression analysis enabled the cell-cell communication study of those T-cell subpopulations within the TME context. Second, I aimed to characterize transcriptomic immune landscapes at a large scale within DLBCL tissue. However, RNA sequencing technologies characterize isolated cells from dissociated tissues with a loss of spatial context. I applied spatial transcriptomics, a cutting-edge technology that enables gene expression mapping in formalin-fixed paraffin-embedded samples of DLBCL biopsies, thus preserving their morphological information. I identified distinct anatomically restricted gene expression profiles in DLBCL samples, defying the historical notion of DLBCL diffuse architecture. These profiles can be classified into ecosystems that differ in cellular composition, functional patterns, and neighborhood characteristics. Moreover, their spatially resolved signatures classify patients with different overall survival revealing the prognostic potential of these spatial identities.Third, I evaluated the effects of altering the communication between NK cells and malignant B cells in DLBCL. I performed a functional in vitro assessment of a blocking antibody developed by the pharmaceutical company Servier. The functional assays demonstrated the effect of the molecular candidate in co-culture settings by improving cytotoxic functions of NK cells against tumor cells. These findings highlight the importance of targeting the interaction between effector cells and malignant B cells to develop effective therapies for DLBCL.This multidisciplinary project carried out on human samples provides a deep understanding of the heterogeneity of immune cells in DLBCL microenvironment at a protein and transcriptomic level while considering their spatial organization. Hence, this project holds significant therapeutic potential, by gaining insights into the disease heterogeneity and its impact on clinical outcome. This project could eventually lead to the discovery of new potential biomarkers and effective therapeutic strategies for DLBCL patients
Dubois, Sonia. "Caractérisation de nouveaux régulateurs de l'activation lymphocytaire et de la lymphomagenèse." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T033/document.
Full textThe diffuse large B cell lymphoma (DLBCL) is the most common non Hodgkinien lymphoma. Two main different entities composed the DLBCL : the Activated B Cell-like subtype (ABC DLBCL) witch is the most aggressive and associated with a poor survival prognostic, and the Germinal-Center B Cell subtype (GCB DLBCL). Unlike the GCB DLBCL, ABC DLBCL are characterized by a genetic signature similar to activated B lymphocytes stimulated by their antigen receptor (BCR, B cell receptor) which results from mutations accumulation. As a consequence, ABC DLBCL survival and proliferation requires the constitutive activation of NF-κB transcription factors. Because NF-κB has pleiotropic effect on different tissues, strategies aiming at targeting NF-κB heterodimers might have deleterious consequences on an organism.My project focuses on identifying new modulators involved in antigen receptor mediated NF-κB activation in physiological and pathological condition.We first performed a mass spectrometry analysis and identified the LUBAC (Linear Ubiquitin Chain Assembly Complex) as a new regulator of antigen receptor mediated a NF-κB ctivation and ABC DLBCL survival. Then, we screened a library of one thousand two hundred chemical compounds on DLBCL viability and identified one compound selectively toxic in vitro for the ABC DLBCL subtype. This compound induced ABC DLBCL apoptosis without affected NF-κB signaling. In the future, this compound could be used as a new therapeutic compound for ABC DLBCL
Aitamer, Marine. "Etude de la production de petites vésicules extracellulaires (dont les exosomes) dans les Lymphomes Diffus à Grandes Cellules B (DLBCL), influence de la voie BDNF/TrkB et impact sur la sensibilité des cellules tumorales aux anti-CD20." Thesis, Limoges, 2020. http://aurore.unilim.fr/theses/nxfile/default/d85d9c4c-cc57-4ab9-85be-dc07f311fd84/blobholder:0/2020LIMO0044.pdf.
Full textDiffuse large B-cell lymphoma (DLBCL) is one of the most aggressive and common non-Hodgkin B lymphomasin adults with two major biologically and clinically subgroups (GCB and ABC). Despite the therapeutic advances provided by R-CHOP immunochemotherapy (combination of an anti-CD20, rituximab, with CHOP chemotherapy), 30 to 40% of patients escape or are refractory to treatment. Recent data show that small extracellular vesicles, “small Evs”, released by DLBCL cells carry the CD20 antigen playing as a "decoy receptor" for immunotherapy. The objective of this thesis was to study comparatively the production of these “small EVs” including exosomes, by GCB and ABC cell lines, as well as their role in the escape of tumor cells from complement dependent cytotoxicity (CDC) of rituximab. We have further extended the team's previous work in analyzing the role of the BDNF/TrkB pathway in this process. In this context, production of “small Evs” and their CD20 level were studied in cells treated or not with a TrkB agonist, 7,8-DHF. No significant difference in size and concentration of these vesicles of GCB and ABC type lines was observed. The level of CD20 in “small Evs” was correlated with CD20 surface expression in parental cells, independently of the DLBCL subtype. Interestingly, higher expression of CD20 within these vesicles and the concentration of "small Evs” were found in cultures treated with 7,8-DHF compared to control cultures. We demonstrated in vitro and in vivo (SUDHL4 xenograft in SCID mice) that combination of autologous or heterologous “small Evs” with rituximab protects tumor cells and tumors from the rituximab cytotoxicity. In addition, protection was significantly improved when ”small Evs” were produced by cells treated with 7,8-DHF. Finally, a preliminary study was initiated on the clinical significance of plasma “small Evs” including exosomes, and their CD20 level in patients with DLBCL compared to healthy volunteers (VS). We show for the first time in DLBCL an increase in their peripheral concentration compared to VS. Altogether, our results confirm in vivo the role of “small Evs” in DLBCL cell evasion from immunotherapy that could be modulated by environmental factors as shown in the present study for BDNF/TrkB pathway. Finally, they argue that “small Evs” incliding exosomes could be used as non-invasive biomarkers of tumor burden and expression of therapeutic targets such as CD20, for disease monitoring and therapeutic orientation
Galand, Claire. "Etude de la présence et du rôle des lymphocytes Th17 dans le micro-environnement des lymphomes B murins." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2011. http://tel.archives-ouvertes.fr/tel-00650093.
Full textDubanet, Lydie. "Neurotrophines, survie cellulaire et microenvironnement : cas du lymphome diffus à grandes cellules B." Limoges, 2013. http://aurore.unilim.fr/theses/nxfile/default/50cc5bfc-fe44-48fb-adac-8e0f3d43b95c/blobholder:0/2013LIMO310J.pdf.
Full textMareschal, Sylvain. "Caractérisation multi-omique des Lymphomes B Diffus à Grandes Cellules." Rouen, 2015. http://www.theses.fr/2015ROUES046.
Full textDiffuse large B-cell lymphomas (DLBCLs) are tumors originating in the lymphatic system, accounting for 4 000 new cases per year in France. While much progress has been made regarding their treatment, one of three patients still does not respond to current immuno-chemotherapies. The present work consisted in characterizing these cancers using various high-throughput technologies, in order to identify somatic alterations that could explain this refractoriness or allow it to be suspected at diagnosis. Gene expression profiling had previously identified two subtypes with distinct outcomes, termed « Activated B-Cell like » and « Germinal Center B-cell like », which we were able to identify using a new simple diagnostic test. The development of bioinformatics software to handle CGH array data confirmed several copy number gains and losses in DLBCLs, and led to a more precise characterization of CDKN2A loss. Finally the sequencing of 14 exomes of relapsed or refractory DLBCLs produced an interesting picture of somatic mutations associated with this phenotype, and highlighted several new leads. An extensive review of the bibliography is proposed on each of these three aspects of tumoral genome alteration, as well as several new bioinformatics methods that may be applied to distinct cancer types in a near future
Szablewski, Vanessa. "Rôle des modulateurs épigénétiques dans la physiopathologie des lymphomes B diffus à grandes cellules." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT036.
Full textDiffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma type. DLBCL shows considerable clinical and biological heterogeneity. The international prognostic index (IPI) remains the most used tool to stratify patients in different risk groups but does not reflect DLBCL biological heterogeneity. Therefore, much research is currently focused on the identification of new prognostic markers for more specific patients’ risk stratification and on the development of therapeutic approaches to improve outcome. Epigenetic alterations are involved in lymphoma. Interestingly, epigenetic alterations are reversible and drugs to target some of them have been developed. With the aim to identify new and relevant prognostic factors that allow the stratification of patients with DLBCL we investigated the gene expression profile of 130 epigenetics regulators in two independent cohorts of patients with newly-diagnosed DLBCL homogeneously treated (respectively 233 and 181 cases). Using the Maxstat R function and Benjami-Hochberg multiple testing correction we found that 10 probe sets had a prognostic value for overall survival (OS) including: BRD1, CARM1, BRPF3, CDYL, DNMT3A, DOT1L, HDAC2, PRMT5, SETD8 and SP140. Using multivariate Cox analysis we found that 3 of these genes remained independent prognostic factors: DNMT3A, DOT1L and SETD8. We used these 3 genes to develop a risk score (EpiScore) based on their expression level in the cohort of 233 DLBCL. EpiScore allowed splitting the patients in 3 groups with significant different OS values: group 1 (low risk, low DNMT3A, DOT1L and SETD8 expression), group 2 (intermediate risk, high expression of one of the three genes) and group 3 (high risk, high expression of two or all three genes). EpiScore prognostic value was validated in two other independent cohorts of patients with DLBCL (181 and 69 patients respectively) We then showed that EpiScore was an independent predictor of survival when compared with previously described prognostic factors, such as the IPI, germinal center B cell and activated B cell molecular subgroups, gene expression-based risk score (GERS) and DNA repair score. As gene expression profiling (GEP) is not a technical approach widely performed in routine practise for all DLBCL newly diagnosed we analysed the pattern of expression of the ten epigenetic genes by immunohistochemistry on formalin-fixed paraffin-embedded (FFPE) tissue sections in a cohort of 65 patients with de novo previously untreated DLBCL. Our results indicate that these epigenetic related proteins are commonly overexpressed in DLBCL compared to reactive lymphoid tissues and may be important for DLBCL pathogenesis. We showed that overexpression of CARM1 and DNMT3A was significantly associated with reduced event free survival. We then designed a new risk score Epi-ImmunoScore (Epi-IS) based on the expression level of CARM1 and DNMT3A by immunohistochemistry. Epi-IS was predictive of OS in DLBCL and allowed splitting patients in two groups (high and low risk). Finally, using gene set enrichment analysis (GSEA) an HDAC gene signature was significantly enriched in the DLBCL samples included in the EpiScore high-risk group and that a significant enrichment of genes encoding for HDAC class II, multiple drug resistance and NOTCH pathways in DLBCL samples with DNMT3A overexpression. According to these data, we compared the response to HDAC inhibitor (SAHA) in DLBCL cell lines with high EpiScore versus low EpiScore and showed that DLBCL cell lines with high EpiScore were significantly more sensitive to SAHA than those low EpiScore. We concluded that EpiScore and Epi-IS, easily evaluated in the routine practice on FFPE tissue sections identified high-risk patients with DLBC. We have also recognized relevant therapeutic targets and identified a number of candidate drugs with potential therapeutic efficiency in DLBCL patients. All these findings may orient future preclinical intervention strategies in DLBCL
Dubois, Sydney. "Profilage moléculaire des Lymphomes Diffus à Grandes Cellules B : vers une médecine personnalisée." Rouen, 2016. http://www.theses.fr/2016ROUENR09.
Full textDiffuse Large B Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma, with approximately 4000 new cases per year in France. Over the past decade, high-throughput techniques have revolutionized the genomic landscape of DLBCL. Indeed, gene expression profiling has highlighted different molecular subtypes of DLBCL, Next Generation Sequencing (NGS) has identified recurrent somatic mutations, and comparative genomic hybridization (CGH) has discovered emblematic copy number variations. Importantly, in many cases these alterations impact potentially actionable targets, thus affording novel personalized therapy opportunities. The work presented herein aimed to detail the heterogeneous molecular profiles of LDGCB, focusing on the detection of alterations with strong theranostic impact, in order to better tailor patients’ targeted therapy regimens. First, we demonstrated the possibility of developing a targeted NGS panel, which was informative for the vast majority of patients analyzed and fully applicable in daily clinical practice. Next, the profiles of patients harboring EZH2 or MYD88 mutations were scrutinized given that these alterations are actionable by EZH2 or NFkB pathway inhibitors currently in development. Finally, our work led to the integration of data from diverse molecular profiling techniques in the hopes of isolating more precise subgroups of patients to target, as we advance towards the personalized medicine era in DLBCL
Bellanger, Cynthia. "Bad et circuits autocrines de survie dans les lymphomes diffus à grandes cellules B : implication des neurotrophines." Limoges, 2010. https://aurore.unilim.fr/theses/nxfile/default/76a52126-788d-4ec8-b3c2-a61ddd10cb51/blobholder:0/2010LIMO310M.pdf.
Full textThis work aimed to study the involvement of the pro-apoptotic molecule, Bad, and neuronal growth factors, NGF and BDNF, in malignant cell survival and therapeutic resistance in diffuse large B-cell lymphoma, DLBCL. It was structured around two axis. We first showed, in a retrospective study of biopsy samples of nodal DLBCL, that lower Bad expressions were significantly related to advanced clinical stages of the patients, possibly reflecting its function as tumor suppressor. Moreover, Bad staining was positively correlated with PP1α staining (the catalytic subunit of PP1 involved in activation of Bad). Of note, phosphorylated (inactive) Bad was also noticed in these tumors. Finally, high expression of AIF, involved in caspase-independent cell death, proved to be predictive of a longer overall survival in non–rituximab-treated patients (CHOP). Thus, these results collectively suggest the potential clinical relevance of targeting Bad phosphatases and AIF-mediated mitochondrial apoptosis for future therapeutic strategies. In the second study, we showed expression of neurotrophins, NGF and BDNF, and their low (p75NTR with its co-receptor, sortilin) and high (TrkB gp95) affinity receptors in DLBCL cell lines. Interestingly, we showed for the first time that NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by culture conditions (serum deprivation, anti-BCR, rituximab). Finally recent results on pharmacological inhibition of Trk signalling showed a strong cytotoxicity in DLBCL cell cultures. In summary, our results suggest that a neurotrophin axis may contribute in DLBCL to malignant cell survival
Broséus, Julien. "Approche génomique des syndromes myéloprolifératifs et des lymphomes B-diffus à grandes cellules en rechute." Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0140.
Full textGenomics provided new insights in our knowledge of pathophysiology, diagnostic approach, prognosis and therapeutic perspectives in hematological malignancies. In the first part of this work, we studied a large cohort of Refractory Anemia with Ring sideroblasts and marked Thrombocytosis (RARS-T). We demonstrated that RARS-T can be considered as an independent entity, with a specific molecular pattern, associating : (i) SF3B1 mutations in more than 85% of cases, accounting for its myelodysplastic aspect and (ii) JAK2 mutations, accounting for its myeloproliferative aspect in more than 50% of cases. Future prospects of the first part of this work is to identify (the) mutation(s) responsible for the myeloproliferative part of JAK2WT RARS-T. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults. In the second part of this work, we performed SNP-array analysis of a homogeneous series of samples from the CORAL cohort, an international prognostic study on relapsed DLBCLs. Our purpose was to identify Copy Number Variations (CNV) associated ER or LR. ER DLBCLs are associated with high rates of CNVs affecting regulators of cell cycle, apoptosis and transcription. In LR DLBCLs, CNVs are related to immune response and cell proliferation. This study provides new insights into the genetic aberrations in relapsed DLBCLs and open up new therapeutic perspectives
Touitou, Valérie. "Etude du microenvironnement cellulaire et moléculaire des lymphomes B intra-oculaires : mise au point d'un modèle murin et étude du rôle des lymphocytes T régulateurs naturels." Paris 6, 2010. http://www.theses.fr/2010PA066594.
Full textRolland, Delphine. "Apport des analyses globales dans les lymphomes B : recherche d'anomalies moléculaires pour un ciblage thérapeutique." Lyon 1, 2008. http://www.theses.fr/2008LYO10216.
Full textLymphomas are incurable neoplasia, especially mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL). In our study, we tried to identify new therapeutic targets using 2 different approaches. First, based on the overexpression of their transcripts, two molecular abnormalities were evaluated as potential therapeutic targets in MCL: GST-π and FTase. In vitro, the GST-π nuclear transfer inhibition increased the cytotoxic activities of several drugs. In vitro, the FTase inhibition by tipifarnib induced cell growth arrest, apoptosis and displayed synergistic effects with drugs used in MCL therapies. In MCL xenograffed mice tipifarnib has shown cytostatic activity. In a multicentric clinical phase II study, 1 of 11 patients with refractory MCL displayed complete remission (CR) which was retrospectively predicted by molecular abnormalities highlighted in the initial biopsy. In a second part, a differential proteomic analysis was realized using SELDI-TOF technology in order to discover therapeutic targets in MCL, MZL and SLL. Tissue protein profiles of 58 fresh frozen biopsies (18 MCL, 20 MZL and 20 SLL) were acquired and then analysed by hierarchical clustering. Specific lymphoma proteomic signatures were identified based on the expression of 37 protein peaks. SELDI-assisted protein purification followed by LC-MS/MS allowed us to identify proteins overexpressed in both MCL and SLL tumors. Among them 2 histones, H2B and H4 were identified in MCL and SRP9 in SLL. We described therapeutic targets in B-cell NHL using focalized and global approaches. This targeting can lead to CR even in refractory NHL and are predictable in initial biopsies
David, Amandine. "Coopération de voies oncogéniques dans la lymphomagenèse B dépendante de MYC : rôle de NF-kB." Limoges, 2014. https://aurore.unilim.fr/theses/nxfile/default/433795c0-3079-41a8-a828-9bc555d10da9/blobholder:0/2014LIMO310D.pdf.
Full textRamuz, Olivier. "Identification de marqueurs pronostiques et de cibles thérapeutiques potentielles dans le domaine des lymphomes malins non hodgkiniens." Aix-Marseille 2, 2006. http://www.theses.fr/2006AIX20659.
Full textDandoit, Mylène. "Evaluation de l'impact de la prise en charge thérapeutique sur la survie et la qualité de vie des patients atteints d'un lymphome folliculaire ou d'un lymphome B diffus à grandes cellules." Thesis, Dijon, 2014. http://www.theses.fr/2014DIJOS038/document.
Full textIn France, hematologic malignancies, which are the sixthmost common cancers, are amajor public healthproblem. This work aimed to study the impact of the therapeutic management on survival and healt-relatedquality of life (HRQoL) in patients with these hematologic malignancies. The first objective of this work is topresent an overview of the epidemiology of lymphoid malignancies with a study of changes in the incidenceand net survival in the Côte d’Or department between 1980 and 2009. The incidence, which has increased since1980, seems to have stabilized since the 2000s for some entities, including follicular lymphoma (FL) and diffuselarge B-cell lymphoma (DLBCL). Overall, we observed an improvement in net survival, with, however, a lessfavorable prognosis in the short and long-term for some entities. FL and DLBCL were the first lymphomas tobenefit from the introduction of monoclonal antibodies in their therapeutic management. Our second studyaimed to assess the impact of rituximab on overall survival in patients with FL or DLBCL in the Côte d’Or departmentusing a methodology based on the propensity score. Our results confirmed the significant benefit ofrituximab on overall survival in an unselected population of patients. In view of these results, we studied theHRQoL of these patients during and after treatment. HRQoL evolved differently during follow-up dependingon the type of lymphoma
Morio, Floriane. "Ciblage préclinique CD22 canin pour l'imagerie phénotypique (immuno-TEMP) et la radioimmunothérapie des chiens spontanément atteints de lymphomes B diffus à grandes cellules." Thesis, Nantes, Ecole nationale vétérinaire, 2019. http://www.theses.fr/2019ONIR130F.
Full textRadioimmunotherapy (RIT) uses radiolabeled monoclonal antibodies (MAbs) specific for tumor antigens. After intravenous injection, radiolabeled MAbs bind to the tumor and produce local irradiation to reduce disseminated tumors. Anti-CD22 RIT has been shown to be effective in clinical trials in patients with diffuse large B-cell lymphoma (DLBCL). The optimization of this therapeutic approach towards personalized treatment requires the development of relevant preclinical models. The mouse models available are of little relevance for optimizing this therapeutic approach. Conversely, dogs with spontaneous DLBCL are representative of human pathology from a physiopathological point of view and constitute a relevant preclinical model for optimizing anti-CD22 RIT in humans. Among the 7 murine anti-canine CD22 Mabs isolated in the laboratory, we chose the most suitable for diagnosis in immunohistochemistry and functional imaging in dogs. The biodistribution of this indium-111 radiolabeled 10C6 antibody has been determinated in healthy and diseased dogs, and dosimetry from imaging data indicates that RIT can be safely performed in dogs with DLBCL. The influence of the specific activity of radiolabeled MAb on biodistribution has been studied. The large variations in the doses deposited to tumors and healthy organs indicate that the specific activity is a parameter to take into account to optimize the efficiency of the RIT in a personalization approach to treatment
Degaud, Michaël. "Rôle de TET2 dans la différenciation terminale des lymphocytes B et implication dans la lymphomagenèse B." Electronic Thesis or Diss., université Paris-Saclay, 2023. http://www.theses.fr/2023UPASL155.
Full textThe TET2 gene controls gene expression by regulating DNA methylation and interacting with other proteins that control the epigenetic landscape. Inactivating mutations in TET2 are found in a wide variety of human hematologic disorders, and in approximately 10% of diffuse large B- cell lymphomas (DLBCLs). These lymphomas develop from B lymphocytes engaged in the germinal center (GC) reaction, an adaptive immunity maturation process that leads to the generation of memory B-cells (MBCs) and plasma cells. After immunization, Tet2-KO mice show a decrease in antigen-specific IgG1-producing plasma cells in the bone marrow. Tet2 inactivation prevents B-cell exit from the GC, plasma cell differentiation and predisposes to lymphoma. In this thesis, I investigated the consequences of Tet2 inactivation on the GC reaction and the development of DLBCL. After two immunizations, we found a higher frequency of IgG1+ GC B-cells, associated with stronger IgG1 membrane expression in Tet2-KO mice, compared to wild-type mice. An in vitro differentiation model showed that Tet2-KO IgG1+ B-cells accumulate and do not engage in plasma cell differentiation. Tet2-KO IgG1+ GC B-cells show, as compared to wild-type cells, increased expression and nuclear translocation of c-Rel, a transcription factor of the NF-κB pathway, associated with decreased transcription of Nfkbia (encoding IκBα), a retrocontrol of the NF-κB pathway. Methylation data from GC B-cells show, in Tet2-KO mice, hypermethylation of the Nfkbia promoter, which would explain the reduced expression. The use of shRNA directed against Nfkbia in the in vitro differentiation model on Tet2-WT B-cells results in an increase in the percentage of IgG1+ GC B-cells. We also showed a decrease in T-bet transcription factor expression in Tet2-KO IgG1+ GC B-cells and IgG1+ MBC, which seems to be involved in abnormalities in MBC differentiation observed in Tet2-KO mice. Indeed, after a single immunization, we observed a decrease in the percentage of IgG1+ CD80hi MBCs, which show a marked preference for differentiation into plasma cells during a recall response, and conversely an increase in the percentage of IgG1+ CD80lo MBCs, which tend to differentiate into GC B-cells during a recall response. In humans, TET2-mutant DLBCL often express an IgG BCR and are characterized by a transcriptomic signature close to that of GC B-cells. Our results suggest that the Tet2-KO IgG1+ GC B-cells exhibit features of these lymphomas, which would pre-exist to complete transformation. With this work, we propose a mechanism to explain the development of DLBCLs from B lymphocytes carrying a TET2 alteration and suggest that c-Rel may be a potential therapeutic target for the treatment of these lymphomas
Gapihan, Guillaume. "Etude du cluster oncogénique miR17-92 dans les lymphomes B agressifs humains." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC321.
Full textPrimary mediastinal large B-cell lymphoma (PMBL) shares pathological features with diffuselarge B-cell lymphoma (DLBCL), and molecular features with classical Hodgkin lymphoma (cHL). The miR-17-92 oncogenic cluster, located at chromosome 13q31, is a region that is amplified in DLBCL. Here we compared the expression of each member of the miR-17-92 oncogenic cluster insamples from 40 PMBL patients versus 20 DLBCL and 20 cHL patients, and studied the target genes linked to deregulated miRNA in PMBL. We found a higher level of miR-92a in PMBL than in DLBCL, but not in cHL. Acombination of in silico prediction and transcriptomic analyses enabled us to identify FOXP1 as a main miR-92a target gene in PMBL, a result so far not established. This was confirmed by 3’UTR, and RNA and protein expressions in transduced cell lines. In vivo studies using the transduced cell lines in mice enabled us to demonstrate a tumor suppressor effect of miR-92aand an oncogenic effect of FOXP1. The higher expression of miR-92a and the down regulation of FOXP1 mRNA and proteinwere also found in human samples of PMBL, while miR-92a expression was low and FOXP1was high in DLBCL. We concluded to a post-transcriptional regulation by miR-92a through FOXP1 targeting in PMBL, with a clinico-pathological relevance for better characterisation of PMBL
Duhamel, Marianne. "Régulation épigénétique de l'expression du facteur de transcription hématopoïétique Aiolos et implication dans la leucémie lymphoïde chronique." Phd thesis, AgroParisTech, 2007. http://pastel.archives-ouvertes.fr/pastel-00003066.
Full textManfroi, Benoît. "Rôle de la molécule APRIL dans le développement des hémopathies malignes B." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV040/document.
Full textTumor microenvironment remains largely ill-defined and clinically underused, as all currently used tumoricidal agents act directly on tumor cells. However it is well known that tumor cells depend on their environment to fully develop. This thesis project focused on the molecule “a proliferation inducing ligand” (APRIL) which is involved in B-cell survival, proliferation and differentiation. Its pathological role was investigated in diffuse large B-cell lymphoma (DLBCL) and in multiple myeloma (MM). Thanks to a murine model we have been able to demonstrate the direct pro-tumoral role of APRIL in DLBCL development. In patients APRIL is of paracrine origin, being produced by myeloid cells and acting on tumor cells. Intra-tumoral expression is variable and a high level of APRIL expression correlates with a poor prognosis. APRIL expression is controlled by chemotactic mechanisms. Differential expression of certain chemokines by tumor cells influence APRIL-producing cells recruitment. We also showed that APRIL has an atypical way of signaling in DLBCL. Tumor cells need to internalize APRIL in order to activate BCMA, a signaling receptor which is mainly expressed intracellularly. In MM, APRIL also possesses a direct pro-tumoral effect as demonstrated in a mouse model. In patients, APRIL is of paracrine origin and mainly expressed by immature myeloid cells. Despite tumor-cell infiltration into the bone marrow APRIL expression remains stable thanks to microenvironment remodeling. A mouse model allowed us to identify an autocrine loop based on interleukin-6 which allows persistence of immature myeloid cells during tumor development, providing a stable expression of the pro-tumoral factor APRIL. Globally, our work identified APRIL as a predictive biomarker with a therapeutic value in DLBCL. Characterization of molecular mechanisms controlling differential expression of APRIL opens new therapeutic perspectives by its antagonism. APRIL also possesses a therapeutic value in MM; characterization of the cellular source for APRIL and interleukin-6, two pro-tumoral factors in MM, has led us to new therapeutic perspectives
Uhel, Fabrice. "Cellules suppressives d'origine myéloïde au cours du sepsis." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B002/document.
Full textSepsis results in a sustained immune dysfunction responsible for poor prognosis and nosocomial infections. Sepsis physiology remains poorly understood and no treatment exists currently, excepted from antibiotherapy and life-support techniques. We asked if myeloid cells could play a role in this sustained immune dysfunction. We demonstrated that Peripheral CD14+HLA-DRlow/- monocytic-myeloid-derived suppressor cells (MDSCs) and CD14-CD15+ low-density granulocytes identified as granulocytic- (G-)MDSCs were increased in septic patients. In vitro, arginase and IDO activities relied on MDSCs and depletion of both subsets restored T-cell proliferation. The initial proportion of G-MDSC predicted occurrence of nosocomial infections. Similarly, high plasma Indoleamine 2,3-dioxygenase (IDO) activity and arginase 1 level were associated with poor outcome. Altogether, our results demonstrate that myeloid cells acquire suppressive functions during sepsis, partially responsible for the sustained immune dysfunction and poor outcome. MDSCs may become a future therapeutic target to restore the immune capacities of septic patients
Pichard, Alexandre. "Etude d'un nouvel anticorps anti-CD37 radiomarqué au Lutétium-177 dans le traitement du lymphome B non hodgkinien : efficacité thérapeutique et mécanismes d'action." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT212/document.
Full textCurrently, B-cell Non-Hodgkin Lymphoma (NHL) treatment relies on the anti-CD20 antibody rituximab and chemotherapy. However, some patients become refractory to this therapy. Here, the effect of the novel anti-CD37 antibody-radionuclide conjugate 177Lu-lilotomab (Betalutin®) was investigated in NHL preclinical models and compared to 177Lu-labeled rituximab (anti-CD20 antibody). We developed a radiobiological approach that discriminates between the cytotoxic effects of unlabeled antibodies and of radiation in human lymphoma cell lines. This method allowed showing that in vitro, rituximab and 177Lu-rituximab were more cytotoxic than lilotomab and 177Lu-lilotomab in the radioresistant Ramos Burkitt’s lymphoma cell line. Conversely, 177Lu-rituximab and 177Lu-lilotomab had similar efficacy in the radiosensitive follicular lymphoma DOHH2 cell line. Their cytotoxicity was lower in mantle cell lymphoma Rec-1 cells that are less radiosensitive than DOHH2 cells. These results were confirmed in vivo in mice treated by intravenous injection of these antibodies after subcutaneous xenografts of Ramos or DOHH2 cells. 177Lu-lilotomab and 177Lu-rituximab showed the same therapeutic efficacy in mice xenografted with radiosensitive DOHH2 cells, although unlabeled lilotomab was less efficient than rituximab. Conversely, in mice xenografted with radioresistant Ramos cells, the lower efficacy of 177Lu-lilotomab compared with 177Lu-rituximab could only be compensated by increasing 177Lu-lilotomab tumor absorbed dose. Mechanistically, the tumor cell response to radiation depended on the cell apoptotic response and reduction of G2/M cell cycle arrest through WEE-1 and MYT1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1) at tyrosine 15 and threonine 14. These results indicate that the synergistic interaction between 177Lu irradiation and lilotomab cytotoxic effects in tumors with reduced CDK1 phosphorylation levels can correct the lower therapeutic efficacy of lilotomab compared with rituximab
Bouzelfen, Abdelilah. "Étude du gène HACE1 dans les lymphomes B." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR012/document.
Full textSeveral B-cell lymphomas have characteristic genetic abnormalities that are important in determining their biologic features and can be useful in differential diagnosis. Historically, classical Hodgkin lymphomas have been distinguished from non-Hodgkin lymphomas (NHL). The most common types are follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), which together make up more than 60% of all lymphomas. DBCL are aggressive but potentially curable with multi-agent chemotherapy. However the putative tumor suppressor genes (TSG) responsible for lymphomagenesis still remain unknown. The rational of this project was based on unpublished data from the translational project GHEDI (Deciphering the Genetic Heterogeneity of Diffuse large B-cell lymphoma in the rituximab era). Array comparative genomic hybridization (aCGH) (Agilent 180 K) was performed in a series of 202 DLBCL and found 40% of deletions of 6q21 region, whose minimal commune deleted region (MCR) contains HACE1 gene. Furthermore, transcriptomic analysis showed a significant correlation between gene copy number and expression level. HACE1, located on chromosome 6q, encodes an E3 ubiquitin ligase and is downregulated in human tumors such as neuroblastomas and natural killer (NK) lymphomas. HACE1 has been shown to ubiquitylate Rac1, a protein involved in cell proliferation and G2/M cell cycle progression. The function of HACE1 and the factors involved in its transcriptional regulation are largely unknown in the context of B-cell lymphomas. In this study, we investigated whether HACE1 is a candidate gene in the 6q genomic region involved in DLBCL lymphomagenesis. We determined the frequency of HACE1 inactivation in B-cell lymphoma and analyzed the mechanisms involved in its silencing. We show, by RT-qPCR, that HACE1 gene is constitutively expressed in normal lymph nodes and in normal B-cells isolated from peripheral blood, contrasting with a strong downregulation of its expression in more than 70% (77/111) of B-cell lymphoma cases and in four tested B-Lymphoma cell lines. HACE1 gene copy number was assessed by quantitative multiplex PCR of short fluorescent fragments (QMPSF) and array for comparative genomic hybridization (aCGH) in 91 DLBCL cases
Mounier, Morgane. "Apport des méthodes de survie nette dans le pronostic des lymphomes malins non hodgkiniens en population générale." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10120/document.
Full textThe net survival of cancer patients in population studies is the most relevant indicator to assess the overall efficiency of the healthcare system of a country. Net survival is defined as the survival that would be observed if the sole cause of death were cancer. This concept is crucial in comparative studies (between geographical areas and/or periods of diagnosis) that estimate specific variations of cancer-related deaths. Net survival takes into account potential differences in mortality patterns between groups. Currently, two methods provide unbiased estimations of net survival: the non-parametric estimator of Pohar-Perme and the parametric model adjusted on specific covariates (mainly, the age at diagnosis). Moreover, new improved parametric tools, such as flexible models, can model the complex covariate effects on mortality. In this work, we modeled the excess mortality rate after a non Hodgkin lymphoma diagnosis, with a model developed by Remontet et al. In addition, we used an appropriate model-building-strategy to model jointly the complex effects of some covariates (such as the time elapsed since diagnosis, the year of diagnosis, and age) on the excess mortality. Finally, this approach allowed for the covariate effects on the net survival and on the excess mortality rate. We applied this method to two different collaborative databases: first on the French database FRANCIM (1995 to 2010) to study the excess mortality after diagnosis of follicular lymphoma, then on the European data of EUROCARE-5 (1996 to 2004) to study the excess mortality after diagnosis of follicular lymphoma and diffuse large B-cell lymphoma. According to the results, the dynamics of the excess mortality rate varies over the time elapsed since diagnosis according to the lymphoma subtype, the age, and the geographical area. The trends of these dynamics over the years of diagnosis are different too
Saad, Faten. "Etude in vivo du rôle de la région régulatrice en 3' du locus des chaînes lourdes d'immunoglobulines dans les réactions inflammatoires et la lymphomagenèse B." Thesis, Limoges, 2015. http://www.theses.fr/2015LIMO0030/document.
Full textB-cell maturation is under the control of the cis-regulatory elements of Ig genes. The four transcripional enhancers (hs3a, hs1,2, hs3b and hs4) of the mouse IgH 3’ regulatory region (3’RR) are the key elements for somatic hypermutation (SHM) and class-switch recombination (CSR). The 3'RR also stimulates Ig transcription during the mature B-cell stage. When associated with an oncogene, the 3’RR is a potent deregulator leading to B-cell lymphomas. Currently nothing is known about its role in the development of immune and inflammatory reactions. During my thesis, we have studied the impact of the 3’RR deletion on the development of inflammatory reactions in response to pristane in BALB/c mice. These studies have allowed us to show that the lack of the 3'RR does not disturb the development of an efficient inflammatory reaction in response to pristane (kinetics of appearance of ascites, volume, cellularity, recruitment of inflammatory cells and their capacity to produce inflammatory and anti-inflammatory cytokines). This suggests the presence of B-cells physiologically capable to induce/spread/maintain a robust and efficient inflammatory immune response. After studying the role of the deletion of the 3'RR in an inflammatory context we have investigated the role of the 3’RR in a lymphomagenesis. For this we brought the 3’RR deficiency in a genetic background able to develop mature B-cell lymphomas (Igλ-Myc mice). While wt mice develop mature and immature B-cell lymphomas, 3’RR-deficient mice exhibit a strong preference for immature lymphomas. Furthermore 3’RR-deficiency leads to a lowered frequency of CD43+ activated B-cell lymphomas and to an increased frequency of CD5+ B-cell lymphomas. CSR and SHM are abrogated in 3’RR-deficient mice lowering the probability of oncogenic mutations during these stages. Pharmacological targeting of 3'RR to block its transcriptional pro-oncogenic effect on translocated oncogene into IgH locus might be a promising approach for the treatment of some mature human B-cell lymphomas
El, amine Rawan. "Effets des protéines virales sur l’organisation nucléaire des lymphocytes B du sang périphérique humain." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS505/document.
Full textAn infection with the Human immunodeficiency virus (HIV) is associated with Bcell lymphomas in infected patients. The incidence of some lymphomas remains elevated in HIVinfected individuals whose immune function has been reconstituted under combined antiretroviral therapy. Its contribution to B-cell oncogenesis cells remains enigmatic. HIV-1 is known to induce an oxidative stress and DNA damage (DD) in infected cells via multiple mechanisms. However, it does not infect B lymphocytes. This contrasts with the viral transactivator protein Tat which circulates in the blood of infected individuals and spontaneously penetrates even non infectable cells. We have detected high levels of reactive oxygen species (ROS), mainly from mitochondria, and DDs in Bcells of HIV-infected individuals. We have thus hypothesized that Tat could induce oxidative DD in B-cells thereby promoting genetic instability and malignant transformation in these cells.In B-cells isolated from peripheral blood of healthy donors and incubated in the presence of purified recombinant protein Tat, an oxidative stress has been induced, the antioxidant capacity was decreased due to diminished glutathione levels, the transcription factor NF-κB was activated, and DD and chromosomal aberrations induced. All the effects induced by Tat were shown to depend on its transcriptional activity. To better understand the mechanism(s) of action of this viral protein, crude extracts from endemic plants of Lebanon were tested for their antioxidant potential. The prooxidative effect of Tat was inhibited, as well as the DD and chromosoml aberrations induced by the viral protein. In conclusion, we propose that the oxidative DNA damage and chromosomal aberrations induced by the Tat protein correspond to novel oncogenic factors that favor the development of B-cell lymphomas in HIV-1 infected individuals
Tanrıver, Gamze. "Modélisation moléculaire des modifications post-translationnelles dans Bcl-xL et des sels de céténiminium." Electronic Thesis or Diss., Université de Lorraine, 2021. http://www.theses.fr/2021LORR0302.
Full textIn recent years, computation chemistry plays important role in order to understand and give insight on structural properties of systems (protein, small molecules etc.) by mimicking their environment. This dissertation consists of two main topics, namely understanding impact of Bcl-xL deamidation by means of molecular dynamics (MD) simulations and investigation of keteniminium salt (KI) by quantum mechanical (QM) methods. Investigation of post-translational modifications (PTMs) gains importance to understand their roles on structure and functions of proteins. Deamidation, one of the post-translational modifications is a crucial switch used for regulating the biological function of anti-apoptotic Bcl-xL. In the first part of the thesis, deamidation-induced conformational changes in Bcl-xL were explored to gain insight into its loss of function by performing molecular dynamics (MD) simulations. The outcomes of this study will provide a unique perspective on the underlying mechanism of Bcl-xL deamidation-induced cell death.Keteniminium salt, nitrogen analog of ketene is widely used intermediate for the synthesis of various scaffolds/substances due to its higher electrophilicity, reactivity and regioselectivity. In the second part of the thesis, keteniminium salt was scrutinized from formation to its involved reactions by means of DFT study. Experimentally observed reactivity differences in the [2 + 2] cycloaddition and electrocyclization reactions were rationalized via a range of different analysis techniques. The outcomes of this study are expected to contribute to the understanding of formation and reactivity differences of keteniminium salt and aid synthetic applications